Obesity is associated with many comorbid conditions, inlcuding fatty liver disease and atherosclerosis. In this application we will investigate a novel therapy for obesity, as well as explore the role of adipose differentiation-related protein (ADFP) in obesity-related fatty liver and in atherosclerosis. There are 4 Specific Aims: 1: To examine the role of adipose differentiation-related protein (ADFP) in fatty liver development using adfp-/- mice created in the Pi'slaboratory, by biochemical and physiologic studies of adfp-/- mice, and observing the effect of restoration or overexpression of adfp on fatty liver development. 2: To examine the role of ADFP in atherosclerosis development in (i) mice that have lost adfp expression in a global manner, (ii)mice that have lost the capacity to express adfp in bone marrow-derived cells only, and (iii) mice that express adfp only in their bone marrow-derived cells, using adfp-/- and adfp+/+ mice and appropriate bone marrow transfer experiments. 3: To characterize the metabolic adaptations in mice after their obesity has been reversed by a newly developed adipose vasculature-targeted ablative therapy. 4: To explore the potential of adipose vasculature-targeted ablation as an anti-obesity therapy in a nonhuman primate model. Aim 4 will be performed in collaboration with investigators at the Southwest Foundation for Biomedical Research (SFBR) at San Antonio. ADFP is a lipid droplet protein that has been postulated to be involved in fat cell differentiation. In Preliminary Studies, we inactivated adfp in mice by gene targeting and found that loss of adfp does not affect fat cell differentiationor adipose tissue growth in response to a high-fat diet. Instead adfp-/- mice are protected against fatty liver in response to the diet; ob/ob mice that have inherited the knockout alleles are also protected against fatty liver development. Further, there is good evidence that ADFP is expressed in foam cells in atheromatous lesions and ADFP is postulated to be important in atherosclerosis. Speicifc Aims 1 and 2 will address the role of ADFP in the pathogenesis of fatty liver and atherosclerosis. Finally, in Preliminary Studies we developed a novel therapy for obesity based on the targeted ablation of adipose vasculature. The method was shown to reverse obesity in mice without detectable complications. Specific Aims 2 and 3 will further explore this novel therapy by mechanistic experiments in mice and testing the therapy in nonhuman primates in collaboration with SFBR.